Recently, we found that the thermal response to norepinephrine (NE) differed unexpectedly when it was microdialyzed, rather microinjected, into the preoptic area (PO) of conscious guinea pigs; i.e., NE produced a fall rather than a rise in core temperature (Tco). Our studies showed that the Tco rise following microinjected NE was due largely to prostaglandin E2 (PGE2) released as a result of tissue injury caused by the microinjection procedure itself, and was not due to the drug, i.e., it was artefactual. Our microdialysis data further suggested that there exists a functional antagonism between endogenous NE and PGE2; it appeared that their relative concentrations in the PO might mutually influence Tco. The first aim of this proposed study, therefore, is to evaluate this apparent functional NE- PGE2 antagonism. Various other studies have lately indicated that different responses to NE administration in vivo or application in vitro are activated depending on the NE dose, and that these different effects are mediated by different noradrenergic receptor subtypes. Subtype populations and densities have also been shown to be inconstant, subject to change under certain conditions. Since the different thermoreregulatory effects of centrally administrated NE have also been reported to depend on dosage and various other conditions, the second aim of this proposed study is to determine whether the direction of thermal responses to NE is adrenoceptor subtype-dependent, and to investigate the influence on the thermal response of selected experimental conditions. The third aim of the present study is to delineate the function(s) of NE during fever in the context of the above hypotheses, since the literature on the role of central NE in the febrile response, though extensive, is inconclusive, probably because of the variability of experimental conditions used in all the studies. Evaluation of the intrinsic thermoregulatory effects of this transmitter will be made easier by the availability now of more specific receptor agonists and antagonists and by the use of microdialysis, which minimizes the confounding effects of traumatic reactions that affect other modes of drug administration. The results of this study should help to resolve the discrepancies among earlier findings and clarify the role of NE in the central control of body temperature. They may also be pertinent to other functions in which hypothalamic NE has been implicated, e.g., in the interactions between the neuroendocrine and immune systems.